Intracellular crosstalk mediated by phosphoinositides is fundamentally important for understanding regulation of cellular function. The specific objective of this application is to investigate the role of phosphoinositide 3-kinase (PI3K) in the metabolic regulation of the retina, specifically the glycolytic pathways that activate the pentose phosphate pathway to generate NADPH, which is required for anabolic and antioxidant pathways that are essential for cone survival. We hypothesize that PI3K signaling provides neuroprotection and regulates cellular processes required for promoting and sustaining photoreceptor functionality and viability. The study proposed here will define how PI3K regulates photoreceptor functions. Using genetically modified mice and pharmacological agents, we have documented changes in cellular redox and metabolic gene expression. We also developed methods for manipulating PI3K and pyruvate kinase (PKM2) in the retina and for detecting anabolic functions and cellular redox changes. We will use these methods to determine how PI3K regulates PKM2 activity and other cellular functions. We will study the mechanisms of cone cell death in cone PI3K knockout and other mouse models of cone degeneration (Aim 1). We will test ways to rescue sick and dying cones that are genetically pre-determined to degenerate (Aim 2).